Document Type

Article

Publication Date

5-3-2026

Comments

This article is the author’s final published version in Ophthalmology Science, Volume 6, Issue 7, 2026, Article number 101216.

The published version is available at https://doi.org/10.1016/j.xops.2026.101216. Copyright © 2026 American Academy of Ophthalmology, Inc.

 

Abstract

OBJECTIVE: To report results of the first-in-human trial of intravitreal tropomyosin-related kinase receptor type B (TrkB) agonist BI 754132 in participants with geographic atrophy (GA). To discuss BI 754132 clinical data in the context of the preclinical findings and their translation into human data.

DESIGN: An open-label, uncontrolled, nonrandomized phase I trial (NCT04002310) assessing the safety, tolerability, and pharmacokinetics of BI 754132 in participants with GA supported by preclinical data.

PARTICIPANTS: Participants with GA recruited between July 2019 and August 2022 in the United States and UK.

METHODS: Clinical trial comprising a single rising dose (SRD) part (n = 15) and multiple dose (MD) part (n = 3). Of 18 participants treated, 16 received a single dose of BI 754132 0.3 to 6 mg (SRD, n = 15; MD, n = 1) and 2 received 3 doses each of BI 754132 6 mg (MD part).

MAIN OUTCOME MEASURES: The primary SRD endpoint was the incidence of ocular and systemic dose-limiting events until day 100; the primary MD endpoint was treatment-related adverse events (AEs) until day 155. Exploratory endpoints included change from baseline in best-corrected visual acuity (BCVA), GA lesion area, central retinal thickness, and selected electroretinogram parameters.

RESULTS: Preclinical data supported a potential treatment effect and a favorable safety profile of BI 754132, supporting clinical development. In the phase I study (SRD and MD parts), 12 of 18 (67%) participants had an AE; of which, 4 had ischemic optic neuropathy in the study eye. Considering the frequency of ischemic optic neuropathy in the absence of efficacy data, the benefit-risk assessment of BI 754132 could not be considered as positive, and the clinical study was terminated. There was a mild increase in central retinal thickness (≤25 μm) of all study eyes. No relevant changes in BCVA, GA lesion area, or electroretinogram parameters were noted.

CONCLUSIONS: Clinical data suggested a potential association between BI 754132 and development of ischemic optic neuropathy. Although the underlying mechanisms remain unclear, these data warrant caution during further exploration of TrkB agonism in GA and highlight the role of monitoring safety data during early clinical development, especially when studying new modes of action.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Additional Files
Figure S1.pdf (323 kB)
Figure S2.pdf (285 kB)
Figure S3.pdf (216 kB)
Figure S4.pdf (260 kB)
Figure S5.pdf (227 kB)
Figure S6.pdf (372 kB)
Figure S7.pdf (383 kB)
Figure S8.pdf (383 kB)
Figure S9.pdf (265 kB)
Figure S10.pdf (363 kB)
Figure S11.pdf (108 kB)
Figure S12.pdf (318 kB)
Figure S13.pdf (404 kB)
Figure S14.pdf (300 kB)
Table S1.pdf (74 kB)
Table S2.pdf (65 kB)
Table S3.pdf (65 kB)
Table S4.pdf (66 kB)
Table S5.pdf (121 kB)
Supplementary Material.pdf (356 kB)
Study group members.docx (28 kB)

PubMed ID

42376188

Language

English

Download

Included in

Ophthalmology Commons

Share

COinS